Toll-like receptors (TLR) are pattern recognition receptors that recognize conserved microbial motifs, including peptidoglycan (TLR2), CpG DNA (TLR9), viral RNA (TLR3/7/8), bacterial flagellin (TLR5) and LPS (TLR4). In particular TLR4s are characterized by a ligand-binding extracellular leucine-rich repeat domain and a cytoplasmic Toll-/IL-1R homology domain (Nahori et al., 2005) that recruits intracellular signaling adaptors. Several ligands for TLR4 have been described including lipopolysaccharid (LPS), lipoteichoic acid (LTA), fibronectin, the fustion protein of RSV, taxol and the vaccine adjuvant monophosphoryl lipid A (MPL). Two major signaling pathways associate with TLR4 activation have been described; the MyD88-dependent and TRIF-dependent pathways.
Recently it has been reported that the TLR4 ligand MPL, a derivative of a purified, detoxified glycolipid from the cell wall of Salmonella Minnesota, exhibited, a bias for TRIF-dependent signaling and less MyD88-dependent signaling relative to other TLR4 antagonists, and it was postulated that MPL may induce active repression of MyD88-dependent inflammatory pathways by inducing additional downstream signaling pathways such as the PI3-Kinase pathway. (Mata-Haro et. al. 2007).
A method is provided for inducing a relatively TRIF biased response comprising administering a selected isomer of an aminoalkyl glucosaminide 4-phosphate (AGP). The selective induction of TRIF-dependent signaling by synthetic lipid A mimetic as disclosed herein may allow for the development of vaccine adjuvants or immunomodulators that selectively alter immune responses while mitigating the potentially toxic side effects associated with the induction of inflammatory cytokines/chemokines.